Drug delivery systems and methods

ABSTRACT

Drug delivery systems and methods are disclosed herein. In some embodiments, a drug delivery system can be configured to deliver a drug to a patient in coordination with a physiological parameter of the patient (e.g., the patient&#39;s natural cerebrospinal fluid (CSF) pulsation or the patient&#39;s heart or respiration rate). In some embodiments, a drug delivery system can be configured to use a combination of infusion and aspiration to control delivery of a drug to a patient. Catheters, controllers, and other components for use in the above systems are also disclosed, as are various methods of using such systems.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/151,585 filed on May 11, 2016, which claims priority to U.S.Provisional Application No. 62/159,552 filed on May 11, 2015, U.S.Provisional Application No. 62/239,875 filed on Oct. 10, 2015, and U.S.Provisional Application No. 62/303,403 filed on Mar. 4, 2016, each ofwhich is hereby incorporated herein by reference in its entirety.

FIELD

Systems and methods are disclosed herein for delivering a drug to asubject (e.g., via intrathecal delivery into the cerebrospinal fluid(CSF) or subarachnoid space of the subject's brain or spine).

BACKGROUND

There are many instances in which it may be desirable to deliver a drugto a patient. The term “drug” as used herein refers to any functionalagent that can be delivered to a human or animal subject, includinghormones, stem cells, gene therapies, chemicals, compounds, small andlarge molecules, dyes, antibodies, viruses, therapeutic agents, etc.

Delivery of the drug can be done in a systemic manner, or can betargeted to a particular location or a particular distribution pattern.Targeted drug delivery can be challenging, however, as there are manyinstances in which the intended delivery target is not accessible, ornot accessible in a minimally-invasive manner.

The natural physiology of the patient can also present drug deliverychallenges. For example, achieving a desired or optimal drugdistribution via intrathecal delivery can be difficult, at least in partdue to the natural flow of CSF within the patient, which tends to beoscillatory and pulsatile with little net flow. Traditional techniqueswhich involve delivering a large quantity of a drug to the intrathecalspace and relying on natural diffusion to distribute the drug areinefficient and may be harmful to the patient.

There is a continual need for improved drug delivery systems andmethods.

SUMMARY

Drug delivery systems and methods are disclosed herein. In someembodiments, a drug delivery system can be configured to deliver a drugto a patient in coordination with a physiological parameter of thepatient (e.g., the patient's natural cerebrospinal fluid (CSF) pulsationor the patient's heart or respiration rate). In some embodiments, a drugdelivery system can be configured to use a combination of infusion andaspiration to control delivery of a drug to a patient. Catheters,controllers, and other components for use in the above systems are alsodisclosed, as are various methods of using such systems.

In some embodiments, a drug delivery system includes a catheter havingat least one fluid lumen; a pump configured to infuse fluid through thecatheter; a sensor configured to measure a physiological parameter of apatient; and a controller that controls the pump to coordinate infusionof a drug through the catheter with the physiological parameter measuredby the sensor.

The controller can synchronize infusion frequency with a frequency of apatient's natural intrathecal pulsation as measured by the sensor. Thecontroller can synchronize infusion phase with a phase of a patient'snatural intrathecal pulsation as measured by the sensor. The controllercan establish a sinusoidal approximation of the patient's naturalintrathecal pulsation as measured by the sensor. The controller cansynchronize infusions with the ascending wave of the sinusoidalapproximation. The controller can synchronize infusions with thedescending wave of the sinusoidal approximation. The sensor can beconfigured to measure intrathecal pressure. The sensor can include afirst sensor configured to measure intrathecal pressure and a secondsensor configured to measure heart rate. The controller can be operablein a learning mode in which no infusion is performed and the controllerestablishes a correlation between heart rate and intrathecal pressurebased on the output of the first and second sensors; and an infusionmode in which the controller coordinates infusion of the drug throughthe catheter with the intrathecal pulsation of the patient based on theoutput of the second sensor. The system can include an implantableinfusion port in fluid communication with the catheter and anextracorporeal injector configured to mate with the infusion port. Thecatheter can include first and second fluid lumens. The controller canbe configured to control the pump to alternately aspirate fluid throughthe first fluid lumen and infuse fluid through the second fluid lumen incoordination with the physiological parameter measured by the sensor.The sensor can be configured to measure at least one of heart rate,intrathecal pressure, intrathecal pulsation rate, respiration rate, lungcapacity, chest expansion, chest contraction, intrathoracic pressure,and intraabdominal pressure.

In some embodiments, a method of delivering a drug to a patient includesinserting a catheter into an intrathecal space of the patient; measuringa physiological parameter of the patient using a sensor; and with acontroller, controlling a pump to coordinate infusion of a drug throughthe catheter with the physiological parameter measured by the sensor.

The method can include synchronizing infusion frequency with a frequencyof the patient's natural intrathecal pulsation as measured by thesensor. The method can include synchronizing infusion phase with a phaseof the patient's natural intrathecal pulsation as measured by thesensor. The method can include establishing a sinusoidal approximationof the patient's natural intrathecal pulsation as measured by the sensorand synchronizing infusions with an ascending wave of the sinusoidalapproximation. The method can include establishing a sinusoidalapproximation of the patient's natural intrathecal pulsation as measuredby the sensor and synchronizing infusions with a descending wave of thesinusoidal approximation. The sensor can be configured to measureintrathecal pressure. The sensor can include a first sensor configuredto measure intrathecal pressure and a second sensor configured tomeasure heart rate. The method can include establishing a correlationbetween heart rate and intrathecal pressure based on the output of thefirst and second sensors when no infusion is performed; and coordinatinginfusion of the drug through the catheter with the intrathecal pulsationof the patient based on the output of the second sensor. The cathetercan include first and second fluid lumens, and the method can includecontrolling the pump to alternately aspirate fluid through the firstfluid lumen and infuse fluid through the second fluid lumen incoordination with the physiological parameter measured by the sensor.The sensor can be configured to measure at least one of heart rate,intrathecal pressure, intrathecal pulsation rate, respiration rate, lungcapacity, chest expansion, chest contraction, intrathoracic pressure,and intraabdominal pressure. The catheter can be inserted such that itextends along the spinal cord of the patient with at least a portion ofthe catheter being disposed in the cervical region of the patient'sspine and at least a portion of the catheter being disposed in thelumbar region of the patient's spine. The method can include deliveringa plurality of different drugs through the catheter, each of the drugsbeing delivered through a respective fluid lumen of the catheter. Themethod can include, with the controller, controlling the pump toaspirate fluid through the catheter. The catheter can include aplurality of outlet ports spaced in a cranial-caudal direction along thelength of the catheter and the method can include infusing a drugthrough a first port of the catheter and aspirating fluid through asecond port of the catheter, the second port being cranial to the firstport. The drug can be infused through a port of the catheter disposed inthe cervical region of the patient's spine to propel the infused druginto the cranial space. The method can include aspirating a volume ofCSF from the patient; infusing a drug through a first, proximal port ofthe catheter while aspirating CSF through a second, distal port of thecatheter to form a bolus of drug between the first and second ports; andinfusing the previously-extracted CSF at a location proximal to thebolus to urge the bolus in a distal direction. The volume of CSFaspirated from the patient can be about 10% by volume of the patient'stotal CSF. The catheter can be inserted through a percutaneous lumbarpuncture in the patient. The infusion can include alternating betweeninfusing a first volume of the drug and aspirating a second volume ofthe drug, the second volume being less than the first volume. The drugcan be delivered to a target region, the target region being at leastone of an intrathecal space of the patient, a subpial region of thepatient, a cerebellum of the patient, a dentate nucleus of the patient,a dorsal root ganglion of the patient, and a motor neuron of thepatient. The drug can include at least one of an antisenseoligonucleotide, a stereopure nucleic acid, a virus, adeno-associatedvirus (AAV), non-viral gene therapy, vexosomes, and liposomes. Themethod can include at least one of performing gene therapy by deliveringthe drug, performing gene editing by delivering the drug, performinggene switching by delivering the drug, and performing non-viral genetherapy by delivering the drug. The method can include determining atotal CSF volume of the patient and tailoring the infusion based on thetotal CSF volume.

In some embodiments, a method of delivering a drug to a patient includesinserting a catheter into an intrathecal space of the patient; with acontroller, controlling a pump to infuse a drug through the catheter;with the controller, controlling the pump to aspirate fluid through thecatheter; and controlling said infusion and said aspiration to targetdelivery of the drug to a target site within the patient.

The infusion can override the natural CSF pulsation of the patient tourge the drug towards the target site. The infusion can coordinate withthe natural CSF pulsation of the patient to urge the drug towards thetarget site. The infusion can include delivering a bolus of the drug andthen performing pulsatile delivery of a fluid behind the bolus to urgethe bolus towards the target site. The fluid can include at least one ofa drug, a buffer solution, and CSF aspirated from the patient throughthe catheter. At least a portion of the catheter can be disposed in thetarget region. At least one of the infusion and the aspiration can becoordinated with a physiological parameter of the patient. Thephysiological parameter can be at least one of heart rate, intrathecalpressure, intrathecal pulsation rate, respiration rate, lung capacity,chest expansion, chest contraction, intrathoracic pressure, andintraabdominal pressure. The catheter can include first and second fluidlumens, and the method can include controlling the pump to alternatelyaspirate fluid through the first fluid lumen and infuse fluid throughthe second fluid lumen. The catheter can be inserted such that itextends along the spinal cord of the patient with at least a portion ofthe catheter being disposed in the cervical region of the patient'sspine and at least a portion of the catheter being disposed in thelumbar region of the patient's spine. The method can include aspiratinga volume of CSF from the patient; infusing a drug through a first,proximal port of the catheter while aspirating CSF through a second,distal port of the catheter to form a bolus of drug between the firstand second ports; and infusing the previously-extracted CSF at alocation proximal to the bolus to urge the bolus in a distal direction.The method can include alternating between infusing a first volume ofthe drug and aspirating a second volume of the drug, the second volumebeing less than the first volume. The target site can be at least one ofan intrathecal space of the patient, a subpial region of the patient, acerebellum of the patient, a dentate nucleus of the patient, a dorsalroot ganglion of the patient, and a motor neuron of the patient. Thedrug can include at least one of an antisense oligonucleotide, astereopure nucleic acid, a virus, adeno-associated virus (AAV),non-viral gene therapy, vexosomes, and liposomes. The method can includeat least one of performing gene therapy by delivering the drug,performing gene editing by delivering the drug, performing geneswitching by delivering the drug, and performing non-viral gene therapyby delivering the drug. The method can include determining a total CSFvolume of the patient and tailoring the infusion and/or the aspirationbased on the total CSF volume.

In some embodiments, a drug delivery catheter includes a tip having afirst fluid lumen that extends to a first fluid port, a second fluidlumen that extends to a second fluid port, and a guidewire lumen; a hub;and a body having a first fluid tube that defines a first fluid lumenthat is in fluid communication with the first fluid lumen of the tip, asecond fluid tube that defines a second fluid lumen that is in fluidcommunication with the second fluid lumen of the tip, a guidewire havinga distal end disposed within the guidewire lumen of the tip, and asheath that defines at least one interior channel in which the guidewireand the first and second fluid tubes are disposed, wherein the sheathextends from a distal end of the hub to a proximal end of the tip.

The tip can have a tapered distal end. The first and second fluid portscan be offset from a central longitudinal axis of the tip. At least oneof the first and second fluid ports can be aimed perpendicular to, or atan oblique angle with respect to, the central longitudinal axis of thetip. The first and second fluid tubes can extend uninterrupted throughthe hub. The first and second fluid tubes can terminate within the hubat respective connectors to which proximal extension tubes can beselectively coupled. The guidewire can extend uninterrupted through thehub. The first and second fluid tubes can have respective fluidconnectors at proximal ends thereof. At least one of the first andsecond fluid tubes can be formed from fused silica. At least one of thefirst and second fluid tubes can be coated in shrink tubing. The sheathcan be formed form polyurethane. The sheath can include an openingformed therein in fluid communication with a fluid port of at least oneof the first and second fluid tubes. At least one of the first andsecond ports can have a helical interior. At least one of the first andsecond ports can have an interior that tapers towards the distal end ofthe port. The first fluid port can be proximal to the second fluid port.The catheter can include an auger rotatably mounted within the catheter.The catheter can include a piezoelectric transducer disposed within thecatheter.

In some embodiments, a percutaneous needle device includes an elongateshaft that defines at least one lumen therein; a sensor disposed at adistal end of the elongate shaft; a display mounted to the elongateshaft configured to display an output of the sensor; and a connectordisposed at a proximal end of the elongate shaft for making a fluidconnection with the at least one lumen.

The device can include a fluid reservoir and a flush dome in fluidcommunication with the lumen of the needle, wherein actuation of theflush dome is effective to pump fluid from the reservoir through thelumen of the needle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a drug delivery system;

FIG. 2 is a perspective view of a catheter that can be used with thesystem of FIG. 1;

FIG. 3A is a perspective view of a tip of the catheter of FIG. 2;

FIG. 3B is a sectional view of the tip of the catheter of FIG. 2;

FIG. 3C is a series of design views of the tip of the catheter of FIG.2;

FIG. 4 is a sectional view of a body of the catheter of FIG. 2;

FIG. 5 is a perspective view of a hub of the catheter of FIG. 2, with aportion of the hub shown as transparent;

FIG. 6A is a sectional view of the hub of FIG. 5, shown with integratedconnectors;

FIG. 6B is an end view of the hub of FIG. 5, shown with integratedconnectors;

FIG. 7A is a plan view of a first bend profile of a guidewire of thecatheter of FIG. 2;

FIG. 7B is a plan view of a second bend profile of a guidewire of thecatheter of FIG. 2;

FIG. 7C is a plan view of a third bend profile of a guidewire of thecatheter of FIG. 2;

FIG. 8A is a perspective, partially-transparent view of a tip that canbe used with the catheter of FIG. 2;

FIG. 8B is a profile, partially-transparent view of the tip of FIG. 8A;

FIG. 9 is a perspective, partially-transparent view of the body of thecatheter of FIG. 2, shown with a side exit port;

FIG. 10 is a perspective and end view of a tip that can be used with thecatheter of FIG. 2;

FIG. 11 is a perspective and end view of a tip that can be used with thecatheter of FIG. 2;

FIG. 12 is a perspective view with a detail, partially-transparent insetof a catheter that can be used with the system of FIG. 1;

FIG. 13 is a perspective view with a detail, partially-transparent insetof a catheter that can be used with the system of FIG. 1;

FIG. 14 is a perspective view with a detail, partially-transparent insetof a catheter that can be used with the system of FIG. 1;

FIG. 15 is a perspective view with a detail, partially-transparent insetof a catheter that can be used with the system of FIG. 1;

FIG. 16 is a schematic view of a focused ultrasound system that can beused with the system of FIG. 1;

FIG. 17 is a schematic hardware diagram of a controller of the system ofFIG. 1;

FIG. 18 is a functional block diagram of the controller of FIG. 17;

FIG. 19 is a screen capture of a graphical user interface that can beimplemented by the controller of FIG. 17;

FIG. 20A is a perspective view of a catheter of the system of FIG. 1implanted in a patient and shown with an infusion port;

FIG. 20B is a perspective schematic view of the catheter and patient ofFIG. 20A;

FIG. 20C is a perspective view of the catheter and patient of FIG. 20A,shown with an infusion port, an injector, and a controller;

FIG. 20D is a perspective view of a distal fluid port of the catheter ofFIG. 20A;

FIG. 20E is a perspective view of a middle or proximal fluid port of thecatheter of FIG. 20A;

FIG. 21A is a diagram illustrating the controller of the system of FIG.1 coordinating control of a pump with a sensed physiological parameter;

FIG. 21B is a diagram illustrating use of the system of FIG. 1 tosynchronize delivery of a drug with an ascending wave of the patient'snatural CSF pulsation;

FIG. 21C is a diagram illustrating use of the system of FIG. 1 tosynchronize delivery of a drug with a descending wave of the patient'snatural CSF pulsation;

FIG. 22 is a schematic diagram of a drug delivery system with a smartlumbar puncture needle; and

FIG. 23 is a schematic diagram of a drug delivery system with manualpumps.

DETAILED DESCRIPTION

Drug delivery systems and methods are disclosed herein. In someembodiments, a drug delivery system can be configured to deliver a drugto a patient in coordination with a physiological parameter of thepatient (e.g., the patient's natural cerebrospinal fluid (CSF) pulsationor the patient's heart or respiration rate). In some embodiments, a drugdelivery system can be configured to use a combination of infusion andaspiration to control delivery of a drug to a patient. Catheters,controllers, and other components for use in the above systems are alsodisclosed, as are various methods of using such systems.

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the structure, function,manufacture, and use of the methods, systems, and devices disclosedherein. One or more examples of these embodiments are illustrated in theaccompanying drawings. Those skilled in the art will understand that themethods, systems, and devices specifically described herein andillustrated in the accompanying drawings are non-limiting exemplaryembodiments. The features illustrated or described in connection withone exemplary embodiment may be combined with the features of otherembodiments. Such modifications and variations are intended to beincluded within the scope of the present disclosure.

In some embodiments, systems and methods are provided in which a drug isinjected or otherwise delivered to the central nervous system of apatient in coordination with the natural CSF flow. For example, the drugcan be injected in a plurality of stages synchronized in phase and/orfrequency with the natural CSF pulse. The systems and methods herein canallow for a drug to be delivered more efficiently to a patient than inthe case of traditional techniques. For example, a smaller quantity ofthe drug can be delivered and still reach the target destination,thereby reducing cost and/or possible side effects of delivering a largequantity of the drug.

The systems and methods disclosed herein can be used in applicationswhere the intended delivery target is not accessible or not accessiblein a minimally-invasive manner, but instead more readily-accessible andsafer injection sites which are in direct fluid communication with theintended delivery site exist. For example, a drug can be delivered tothe intrathecal space of a patient via an injection site in thepatient's spine (e.g., a lumbar region, a thoracic region, a cervicalregion, and so forth) and can be transported via the intrathecal spaceto a target location that is cranial to the injection site (e.g., thebrain or a more-cranial region of the spine). In other embodiments, thedrug can be transported to a location that is caudal to the injectionsite.

The systems and methods disclosed herein can include fully programmablecustomized injection and/or aspiration profiles which can besynchronized by real-time monitoring of physiological parameters of thepatient, such as heart rate, CSF pressure, CSF pulsation rate,respiration rate, lung capacity, chest expansion and contraction,intrathoracic pressure, intraabdominal pressure, and the like. This canallow the end user to fine-tune injection/aspiration doses per cycle,time length and profile of each microinjection, relative timing (orphase) of microinjections, and other parameters. The systems and methodsdisclosed herein can include real-time inline pressure sensing forestimating drug delivery efficiency and ensuring patient safety.

The systems and methods disclosed herein can include custom builtcatheters with various lumen quantities, lumen sizes, port placementlocations, and other properties. The catheters can bedirectionality-optimized for efficient mixing and/or such that they areadapted for a particular anatomy.

FIG. 1 is a schematic diagram of an exemplary drug delivery system 100.As shown, the system 100 can include a catheter 102, a controller 104, apump or actuator 106, and one or more sensors 108. The pump 106 can beconfigured to pump a drug or a drug-containing fluid through thecatheter 102 and into a patient 110 (e.g., into an intrathecal space ofthe patient). The pump 106 can also be configured to aspirate fluid fromthe patient. The pump 106 can be controlled by the controller 104 tosynchronize or otherwise coordinate delivery of the drug and/oraspiration of fluid with a physiological parameter of the patient, whichcan be measured by the sensor 108. Exemplary physiological parameterscan include heart rate, CSF pressure, CSF pulsation rate, respirationrate, lung capacity, chest expansion and contraction, intrathoracicpressure, intraabdominal pressure, and the like.

An exemplary catheter 102 which can be used with the system 100 is shownin FIG. 2. The catheter 102 can include a tip portion 112, a body 114,and a hub 116. A first portion 114 d of the body 114 can extend betweenthe tip 112 and the distal end of the hub 116. A second portion 114 p ofthe body 114 can extend proximally from the hub 116 to one or moreconnectors 118 or other features for coupling the catheter 102 to thesystem 100, e.g., for attaching the catheter to the pump 106. Thecatheter 102 can have an overall length of about 1 meter.

The tip 112 of the catheter 102 is shown in more detail in FIGS. 3A-3C.The tip 112 can include a generally cylindrical body with a conical,bulleted, or tapered tip. The tip 112 can provide an atraumatic lead-insurface to facilitate tunneling the catheter 102 through tissue orthrough a lumen of the patient, such as the intrathecal space. The tip112 can include one or more fluid lumens formed therein, and acorresponding one or more fluid ports through which fluid can becommunicated from the fluid lumen to an exterior of the catheter andvice-versa. In the illustrated embodiment, the tip 112 includes a firstfluid lumen 120A with a first fluid port 122A and a second fluid lumen120B with a second fluid port 122B, though it will be appreciated thatthe tip can include any number of fluid lumens (e.g., zero, one, two,three, four, five, more than five, etc.) and any number of fluid ports(e.g., zero, one, two, three, four, five, more than five, etc.). Thefluid ports 122A, 122B can be aimed in a substantially distal directionand can be offset from the central longitudinal axis of the tip 112, asshown. In other embodiments, the fluid ports 122A, 122B can be aimedlaterally, e.g., in a direction substantially perpendicular to thecentral longitudinal axis of the tip 112. Having the fluid portsslightly offset from center or aimed laterally can advantageously reducethe risk of the ports becoming occluded during insertion or use of thecatheter 102.

The catheter 102 can include a steering mechanism to facilitate remotepositioning of the catheter within the patient. For example, thecatheter 102 can be configured to receive a guidewire 124 therethroughto allow the catheter to be inserted over the guidewire or to be steeredby the guidewire. In the illustrated embodiment, the tip 112 includes aguidewire lumen 126. The guidewire lumen 126 can be a closed, blind holeas shown, or can be open to an exterior of the tip 112. Alternatively,or in addition, the catheter 102 can include one or more steering wires(not shown) that terminate at the tip 112. The wires can extendproximally from the tip 112 to a proximal end of the catheter 102, wherethey can be selectively tensioned to steer the tip of the catheterwithin the patient. For example, the catheter 102 can include first andsecond steering wires that extend longitudinally therethrough and whichare anchored to the tip 112 at diametrically-opposed locations about theouter periphery of the tip. The steering wires can extend throughrespective sleeves or tubes in the body 114 of the catheter 102 to theproximal end of the catheter where tension can be selectively appliedthereto to steer the tip 112 of the catheter.

The tip 112 can be formed from various materials, includingbiocompatible materials, stainless steel, titanium, ceramics, polymers,and the like. The tip 112 can be radiopaque or can include one or moreradiopaque markers to facilitate visualization under fluoroscopy orother imaging techniques.

The tip 112 can have an outside diameter of about 3 French to about 5French. The tip 112 can have an outside diameter of about 1 mm to about3 mm.

FIG. 4 is a cross-sectional view of the distal portion 114 d of thecatheter body 114. As shown, the body 114 can include an outer sheath128 that defines an interior channel 130. One or more fluid tubes 132A,132B can be disposed within the interior channel, each fluid tubedefining a respective fluid lumen 134A, 134B. The interior channel 130can also contain a guidewire 124 or one or more steering wires (notshown). In the illustrated embodiment, the distal body portion 114 dincludes a first fluid tube 132A having a lumen 134A in fluidcommunication with the first fluid lumen 120A of the tip 112, a secondfluid tube 132B having a lumen 134B in fluid communication with thesecond fluid lumen 120B of the tip, and a guidewire 124.

The sheath 128 can have various cross-sectional profiles. For example,the sheath 128 can have a circular transverse cross-section that definesa single interior channel 130 as shown. By way of further example, thesheath 128 can have multiple interior channels. Each of the fluid tubes132A, 132B can be disposed within its own independent channel of thesheath 128, or the sheath itself can define the fluid tubes. Theguidewire 124 can be disposed in its own independent channel of thesheath 128 and the fluid tubes 132A, 132B can be disposed in a separatechannel of the sheath. The guidewire channel can have a circularcross-section and the fluid tube channel can have a crescent or D-shapedcross-section.

The fluid tubes 132A, 132B can be formed from any of a variety ofmaterials, including fused silica, polyurethane, etc. Use of fusedsilica can be advantageous when using the system 100 to deliver viruses,as viruses may be less prone to sticking to fused silica fluid tubes. Insome embodiments, fluid tubes used for drug delivery can be formed fromfused silica and fluid tubes not used for drug delivery (e.g., bufferdelivery tubes or aspiration tubes) can be formed from a material otherthan fused silica, such as polyurethane. The fluid tubes 132A, 132B canbe coated with a shrink tubing or an outer sheath to provide stress andstrain relief for the fluid tubes. The sheath 128 can be formed from anyof a variety of materials, including polyurethane. While use of thefluid tubes 132A, 132B to communicate fluid is generally describedherein, the fluid tubes can also be used for other purposes, such asinserting a biopsy probe or other instrument, or inserting a sensor 108.

The fluid tubes 132A, 132B can have an inside diameter of about 0.005inches to about 0.050 inches. The fluid tubes 132A, 132B can have aninside diameter of about 0.010 inches to about 0.020 inches. The body114 can have an outside diameter of about 3 French to about 5 French.The body 114 can have an outside diameter of about 1 mm to about 3 mm.

An exemplary hub 116 is shown in FIG. 5. The hub 116 can includerespective channels for receiving the first fluid tube 132A, the secondfluid tube 132B, and the guidewire 124. Each channel can includeproximal and distal openings. The channels can merge within the body ofthe hub 116 such that they each share a common distal opening. Thesheath 128 of the distal body portion 114 d can be received through thedistal opening of the hub 116 and into the guidewire channel of the hub.The fluid tubes 132A, 132B can penetrate the sidewall of the sheath 128within the body of the hub 116. The hub 116 can thus form a seal betweenthe sheath 128 and the fluid tubes 132A, 132B, support the fluid tubesand the guidewire 124, and guide these components into the innerchannel(s) 130 of the sheath of the distal body portion 114 d.

The hub 116 can be a “pass-through” type hub in which the first andsecond fluid tubes 132A, 132B extend completely through the hubuninterrupted as shown in FIG. 5. Alternatively, as shown in FIGS.6A-6B, the first and second fluid tubes 132A, 132B can terminate withinthe hub at respective connector ports 136A, 136B. The connector ports136A, 136B can allow selective coupling and decoupling of the proximalbody portion 114 p (e.g., proximal extension tubes) to the first andsecond fluid tubes 132A, 132B. The guidewire 124 can continue to extendcompletely through the hub 116 uninterrupted, or it too can terminatewithin the hub at a connector where a proximal guide wire extension canbe selectively coupled thereto. Any of a variety of connector types canbe used to couple the fluid tubes to the proximal extension tubes,including zero-dead-volume micro-connectors or fittings available fromValco Instruments Co. Inc. of Houston, Tex.

The proximal body portion 114 p can include a sheath similar to that ofthe distal body portion 114 d, or can be formed by the fluid tubes 132A,132B extending proximally from the hub 116, or from one or moreextension tubes coupled to the fluid tubes 132A, 132B at the hub 116.The proximal end of the catheter 102 can include one or more connectors118 for making a fluid connection with the fluid tubes 132A, 132B of thecatheter. For example, as shown in FIG. 2, the fluid tubes 132A, 132B(or proximal extension tubes as the case may be) can include a connector118 at a proximal end thereof. Any of a variety of connector types canbe used, including zero-dead-volume micro-connectors or fittingsavailable from Valco Instruments Co. Inc. of Houston, Tex.

The guidewire 124 can be disposed within the catheter 102 and can beused to guide, steer, or otherwise control insertion of the catheterinto the patient.

The guidewire 124 can be cylindrical and can have asubstantially-straight profile. The guidewire 124 can extend completelythrough the catheter 102, or can terminate in a blind bore 126 formed inthe tip 112 of the catheter. In use, the guidewire 124 can be insertedinto the patient first and guided to a target site, and the catheter 102can then be inserted over the guidewire to position a portion of thecatheter at the target site. In other embodiments, the catheter 102 canbe inserted before or simultaneously with the guidewire 124, and theguidewire can be used to steer or guide the catheter.

For example, as shown in FIGS. 7A-7C, the guidewire 124 can have aresting configuration that deviates from a straight line at or near adistal end of the guidewire. In FIG. 7A, the guidewire 124 has astraight distal portion 124 d and a straight proximal portion 124 pjoined by a curved elbow such that a central longitudinal axis of thedistal portion extends at an oblique angle with respect to a centrallongitudinal axis of the proximal portion. In FIG. 7B, the guidewire 124has a curved distal portion 124 d joined to a straight proximal portion124 p such that a central longitudinal axis of the distal portionextends at an oblique angle with respect to a central longitudinal axisof the proximal portion. In FIG. 7C, the guidewire 124 has a straightdistal portion 124 d and a straight proximal portion 124 p that meet atan angled bend such that a central longitudinal axis of the distalportion extends at an oblique angle with respect to a centrallongitudinal axis of the proximal portion.

In use, the guidewire 124 can be used to navigate the catheter 102through the patient by twisting the proximal end of the guidewire toturn the bent distal portion and thereby steer or aim the catheter.While a single guidewire 124 is shown, it will be appreciated that thecatheter 102 can include any number of guidewires and/or guidewirelumens. The guidewire 124 can be formed from any of a variety ofmaterials, including shape-memory metals such as Nitinol.

Any of the catheters disclosed herein can be steerable. For example, asteering mechanism can be provided to allow the distal end of thecatheter 102 to be guided during insertion or at another desired time.In some embodiments, the catheter 102 can include one or more steeringwires having a first end coupled to the distal tip 112 of the catheterand having a second end at the proximal end of the catheter throughwhich tension can be selectively applied to the steering wires to director steer the tip of the catheter in a desired direction. The steeringwires can be embedded in the sidewalls of the catheter 102 or can extendthrough a lumen of the catheter.

In some embodiments, the catheter 102 can include a coaxial steeringcatheter (not shown) extending therethrough. A distal end of thesteering catheter can be curved or biased towards a curved shape suchthat, when the steering catheter is deployed distally from the tip ofthe primary catheter 102, the primary catheter can be steered or guidedalong the curve of the steering catheter. The steering catheter can thenbe retracted back into the primary catheter 102 to discontinue thecurved guidance. The steering catheter can be formed from or can includeshape memory or resilient materials such that the steering catheter isdeformable between a substantially straight line configuration whenretracted into the primary catheter 102 and a flexed or curvedconfiguration when deployed from the primary catheter. The steeringcatheter can be longitudinally translatable relative to the primarycatheter 102 to allow for deployment and retraction.

Any of the catheters disclosed herein can include a camera or imagingdevice, which can be integral with the catheter or can be insertedthrough a working channel of the catheter. Any of the cathetersdisclosed herein can include markings visible under fluoroscopy, CT,MRI, or other imaging techniques to allow the catheter to be visualizedin images captured using such techniques.

The catheter 102 can be configured to withstand high internal pressures.The catheter 102 can be configured to withstand a pressure of at leastabout 100 psi, at least about 200 psi, and/or at least about 500 psi.

It will be appreciated that a number of variations on theabove-described catheter 102 are possible. For example, one or more ofthe fluid ports can be aimed to the side such that they exit a lateralsidewall of the catheter. FIGS. 8A-8B illustrate an exemplary cathetertip having side-facing ports. As shown, the tip 112 includes a firstfluid lumen 120A that extends to a distal-facing port 122A. Thedistal-facing port 122A can be formed in an angled or slash-cut distalface of the tip 112. The tip 112 also includes a second fluid lumen 120Bthat extends to a side-facing port 122B. The tip 112 can also include aguidewire lumen for receiving the distal end of a guide wire 124. Insome embodiments, the central channel 130 of the sheath 128 can act as afluid lumen, e.g., for delivering a buffer or for delivering a drug. Thetip 112 can include a side-facing port 122C in fluid communication withthe central channel 130 of the sheath 128.

The catheter 102 can include one or more fluid ports formed proximal tothe tip portion 112 of the catheter, e.g., formed in the body 114 of thecatheter. FIG. 9 illustrates an exemplary catheter body 114 having aside-facing port 122B. As shown, one or more of the fluid tubes 132A,132B extending through the sheath 128 of the body 114 can terminatewithin the body or can otherwise have a fluid port disposed in the body.The sheath 128 can have a slit or opening 122B aligned with the port ofthe fluid tube 132B, such that fluid exiting the fluid tube can flowthrough the opening in the sheath or such that fluid can flow throughthe sheath and into the port of the fluid tube. The catheter 102 caninclude one or more plugs 138 disposed within the channel 130 of thesheath 128 to prevent fluid exiting or entering the fluid tube 132B fromflowing proximally and/or distally within the sheath, instead guidingthe fluid out of the sheath through the opening or slit 122B formedtherein, or guiding incoming fluid into the fluid port of the tube. Theplugs 138 can be formed from a rigid material, from an adhesive,silicone, or various other materials.

The fluid lumens of the catheter can have various internal geometries tocontrol or direct the delivery pattern of fluid delivered therethrough.FIG. 10 illustrates an exemplary catheter tip 112 in which one of thefluid lumens 120A has a thread formed on an interior surface thereof todefine a helical or “corkscrew” shape. The helical shape of the fluidlumen 120A can promote turbulent flow of fluid therefrom encouragingdispersion or even distribution of the fluid. It will be appreciatedthat more than one of the fluid lumens can have a helical tip. FIG. 11illustrates an exemplary catheter tip 112 in which one of the fluidlumens 120A tapers or narrows towards the distal end to create a nozzle.This nozzle can create a jet-stream effect, increasing the velocity ofthe infusate as it is delivered. It will be appreciated that more thanone of the fluid lumens can have a nozzle tip. As also shown in FIGS.10-11, one or more of the fluid lumens can have a simple cylindricaltip.

As noted above, the catheter 102 can include any number of lumensextending therethrough. In some embodiments, a dual-lumen catheter canbe used. The dual lumen catheter can include an infusion lumen and apressure sensor lumen, an infusion lumen and an aspiration lumen, twoinfusion lumens, etc. In other embodiments, a tri-lumen catheter can beused. The tri-lumen catheter can include an infusion lumen, anaspiration lumen, and a pressure sensor lumen, two infusion lumens andan aspiration lumen, three infusion lumens, etc. FIG. 10 illustrates anexemplary tri-lumen catheter having an infusion lumen 120A, anaspiration lumen 120B, and a pressure sensor lumen 120C. FIG. 11illustrates an exemplary dual-lumen catheter an infusion lumen 120A andan aspiration lumen 120B.

The catheter can include a valve system to control the direction offluid flow therethrough. For example, a valve system can include one-wayvalves on each lumen to prevent infusion into an aspiration lumen andvice versa. The valve system can facilitate use of a single syringe orother pump to infuse and withdraw fluid, or can facilitate infusion andaspiration through a single lumen.

As discussed further below, the sensor 108 can be mounted to thecatheter 102, formed integrally with the catheter, threaded through alumen of the catheter, etc. For example, the catheter 102 can include asensor 108 embedded in the tip portion 112 of the catheter, or caninclude a sensor threaded through a dedicated sensor lumen of thecatheter.

One or more of the fluid lumens through the catheter can have fluidports that are longitudinally offset from fluid ports of other lumens ofthe catheter. For example, as shown in FIG. 12, the catheter 102 caninclude a first fluid lumen 120A that extends to a fluid port 122Aformed at the terminal distal end of the catheter. The catheter 102 canalso include a second fluid lumen 120B that extends to fluid ports 122Bwhich are spaced a distance D apart from the distal end of the catheterin a proximal direction. As shown, the second fluid lumen 120B caninclude one or more side-facing ports 122B. In other embodiments, thesecond fluid lumen 120B can include a distal facing port. In use, one ofthe fluid lumens 120A, 120B can be used to deliver a drug or other fluidand the other fluid lumen can be used to aspirate fluid from thepatient. The catheter 102 can thus be used to create a “push-pull”effect at a target site, in which a drug is infused at the distal end ofthe catheter via the first fluid lumen 120A and then drawn back towardthe proximal end of the catheter by the flow of fluid being aspiratedthrough the second fluid lumen 120B. The opposite arrangement can alsobe used, in which the drug is infused through the proximal port(s) andaspirated through the distal port(s). A proximal end of the catheter 102can have first and second connectors 118A, 118B correspondingrespectively to the first and second fluid lumens 120A, 120B. The offsetfluid ports 122A, 122B can be used to coordinate delivery with aphysiological parameter of the patient, such as natural CSF flow. Anexternal peristaltic pump or other device can be used to drive theinfusion and/or aspiration. As shown, the outer sheath 128 of the body114 can taper inward to the first lumen 120A after the termination ofthe second lumen 120B.

The catheter 102 can include features for controlling delivery of fluidthrough the catheter. For example, as shown in FIG. 13, the catheter 102can include an internal auger 140. The auger 140 can have an elongateflexible shaft 142 that extends through the catheter 102 to a proximalend of the catheter, where it can be coupled to a motor for drivingrotation of the auger. The motor can be part of the controller 104 orcan be a separate component. The controller 104 can start and stoprotation of the auger 140, and/or can control the speed or direction ofauger rotation to control delivery of fluid through the fluid lumen 120in which the auger is disposed. The auger 140 can be disposed in a fluidtube 132 extending through a sheath portion 128 of the catheter 102. Theauger 140 can also be disposed distal to a terminal distal end of afluid tube 132, with the auger shaft 142 extending through the fluidtube. The auger 140 can thus be disposed within the sheath 128 of thecatheter 102 but distal to a fluid tube 132 of the catheter. The auger140 can advantageously control fluid delivery through the catheter 102and generate more turbulent flow of fluid from the catheter. A proximalend of the catheter can have first and second connectors 118A, 118Bcorresponding respectively to the first and second fluid lumens and athird port or connector 118C through which the auger shaft 142 canextend. The auger 140 can be used to coordinate delivery with aphysiological parameter of the patient, such as natural CSF flow.

By way of further example, as shown in FIG. 14, the catheter 102 caninclude an internal, reciprocating piston or inner tube 144. Thecatheter 102 can include a fixed outer tube 128 and a slidable innertube 144 disposed coaxially within the outer tube. The inner tube 144can be configured to translate longitudinally with respect to the outertube 128. The inner tube 144 can include a valve 146, e.g., at aterminal distal end thereof. Exemplary valves include one-way valves,duck-bill valves, spring-biased check valves, and the like. A seal canbe formed between the inner tube 144 and the outer tube 128, e.g., at aproximal end of the catheter 102. In use, the inner tube 144 can beloaded with a drug-containing fluid. The inner tube 144 can then bepulled proximally with respect to the outer tube 128 to cause thedrug-containing fluid to flow through a one-way valve 146 into thedistal end of the outer tube. The inner tube 144 can then be pusheddistally, closing the one-way valve 146 and expelling thedrug-containing fluid out of the distal end of the outer tube 128 andinto the patient. The translating tubes 128, 144 can allow a fixed orpredetermined volume of drug-containing infusate to be delivered witheach reciprocation of the inner tube 144. The proximal ends of the outerand inner tubes 128, 144 can include connectors 118A, 118B, e.g., forsupplying fluid to the outer and inner tubes. The reciprocating innertube 144 can be used to coordinate delivery with a physiologicalparameter of the patient, such as natural CSF flow.

As another example, as shown in FIG. 15, the catheter 102 can include atransducer 148, such as a piezoelectric transducer, to help controldelivery of a drug through the catheter. The transducer 148 can beformed on a flex circuit or other substrate disposed adjacent to a fluidport 122 of the catheter 102. The transducer 148 can include anelectrically-conductive lead or wire 150 that extends proximallytherefrom through the catheter 102 to the controller 104. In use, anelectric potential can be applied to the transducer 148 to inducevibration or other movement of the transducer. This movement can controldistribution of the drug from the catheter 102. For example, thetransducer 148 can control the direction in which the infusate flows asit exits the catheter 102, can control the opening or closing of a fluidport 122 of the catheter, and/or can control the volume of infusate thatexits the catheter. A proximal end of the catheter 102 can have firstand second connectors 118A, 118B corresponding respectively to first andsecond fluid lumens and a third port or connector 118C through which theelectrical conductor 150 of the transducer 148 can extend. Thetransducer 148 can be used to coordinate delivery with a physiologicalparameter of the patient, such as natural CSF flow.

The system 100 can include one or more transducers for deliveringfocused ultrasound to the patient. As shown in FIG. 16, a focusedultrasound system 152 can aim ultrasonic waves toward a location atwhich drug-containing infusate 154 exits the catheter 102. The focusedultrasound can enhance dispersion of the drug, and/or control thedirection and degree to which the drug disperses. Focused ultrasound canbe used to coordinate delivery with a physiological parameter of thepatient, such as natural CSF flow. Focused ultrasound can also be usedto enhance or direct drug distribution without pulsatile delivery.

FIG. 17 illustrates a block diagram of the physical components of anexemplary embodiment of the controller 104. Although an exemplarycontroller 104 is depicted and described herein, it will be appreciatedthat this is for sake of generality and convenience. In otherembodiments, the controller 104 may differ in architecture and operationfrom that shown and described here. The controller 104 can be a tabletcomputer, mobile device, smart phone, laptop computer, desktop computer,cloud-based computer, server computer, and so forth. One or moreportions of the controller 104 can be implanted in the patient. Deliverycontrol software can execute on the controller 104. The software canexecute on a local hardware component (e.g., a tablet computer, smartphone, laptop computer, or the like) or can execute remotely (e.g., on aserver or cloud-connected computing device in communications couplingwith the controller).

The illustrated controller 104 includes a processor 156 which controlsthe operation of the controller 104, for example by executing embeddedsoftware, operating systems, device drivers, application programs, andso forth. The processor 156 can include any type of microprocessor orcentral processing unit (CPU), including programmable general-purpose orspecial-purpose processors and/or any of a variety of proprietary orcommercially-available single or multi-processor systems. As usedherein, the term processor can refer to microprocessors,microcontrollers, ASICs, FPGAs, PICs, processors that read and interpretprogram instructions from internal or external memory or registers, andso forth. The controller 104 also includes a memory 158, which providestemporary or permanent storage for code to be executed by the processor156 or for data that is processed by the processor. The memory 158 caninclude read-only memory (ROM), flash memory, one or more varieties ofrandom access memory (RAM), and/or a combination of memory technologies.The various components of the controller 104 can be interconnected viaany one or more separate traces, physical busses, communication lines,etc.

The controller 104 can also include an interface 160, such as acommunication interface or an I/O interface. A communication interfacecan enable the controller 104 to communicate with remote devices (e.g.,other controllers or computer systems) over a network or communicationsbus (e.g., a universal serial bus). An I/O interface can facilitatecommunication between one or more input devices, one or more outputdevices, and the various other components of the controller 104.Exemplary input devices include touch screens, mechanical buttons,keyboards, and pointing devices. The controller 104 can also include astorage device 162, which can include any conventional medium forstoring data in a non-volatile and/or non-transient manner. The storagedevice 162 can thus hold data and/or instructions in a persistent state(i.e., the value is retained despite interruption of power to thecontroller 104). The storage device 162 can include one or more harddisk drives, flash drives, USB drives, optical drives, various mediadisks or cards, and/or any combination thereof and can be directlyconnected to the other components of the controller 104 or remotelyconnected thereto, such as through the communication interface. Thecontroller 104 can also include a display 164, and can generate imagesto be displayed thereon. In some embodiments, the display 164 can be avacuum fluorescent display (VFD), an organic light-emitting diode (OLED)display, or a liquid crystal display (LCD). The controller 104 can alsoinclude a power supply 166 and appropriate regulating and conditioningcircuitry. Exemplary power supplies include batteries, such as polymerlithium ion batteries, or adapters for coupling the controller 104 to aDC or AC power source (e.g., a USB adapter or a wall adapter).

The various functions performed by the controller 104 can be logicallydescribed as being performed by one or more modules. It will beappreciated that such modules can be implemented in hardware, software,or a combination thereof. It will further be appreciated that, whenimplemented in software, modules can be part of a single program or oneor more separate programs, and can be implemented in a variety ofcontexts (e.g., as part of an embedded software package, an operatingsystem, a device driver, a standalone application, and/or combinationsthereof). In addition, software embodying one or more modules can bestored as an executable program on one or more non-transitorycomputer-readable storage mediums. Functions disclosed herein as beingperformed by a particular module can also be performed by any othermodule or combination of modules, and the controller can include feweror more modules than what is shown and described herein. FIG. 18 is aschematic diagram of the modules of one exemplary embodiment of thecontroller 104.

As shown in FIG. 18, the controller 104 can include a sensor inputmodule 168 configured to receive information from the sensor(s) 108. Thesensor input module 168 can read and interpret output signals suppliedfrom the sensors 108 to the processor 156, e.g., via a general purposeinput/output pin of the processor. The sensor input module 168 canoptionally perform various processing on the sensor signals, such asfrequency detection, phase detection, debouncing, analog-to-digitalconversion, filtering, and so forth.

The controller 104 can also include a delivery control module 170configured to control the pump or actuator 106 to infuse or aspiratefluid from the patient and/or to control the catheter 102 (e.g., anauger, piston, transducer, ultrasound system, etc.). For example, whenan “infuse” instruction is issued, the delivery control module 170 cancause power to be supplied to the pump 106 to begin pumping infusatethrough the catheter 102, or cause an electronically-actuated valve toopen such that infusate stored under pressure is placed in fluidcommunication with the catheter and flows therethrough. In someembodiments, the delivery control module 170 can be configured to cutoff power to the pump 106 or to close a valve when a pressure sensorindicates that the pressure in the system has reached a predeterminedthreshold amount. When an “aspirate” instruction is issued, the deliverycontrol module 170 can cause power to be supplied to the pump 106 tobegin pumping fluid out of the catheter 102.

The controller 104 can include a user input module 172 configured toreceive one or more user inputs, e.g., as supplied by a user via theinterface 160. Exemplary user inputs can include infusion parameters,patient information, treatment protocols, and so forth, as discussedfurther below.

The controller 104 can also include a display module 174 configured todisplay various information to the user on the display 164, such as agraphical or textual user interface, menus, buttons, instructions, andother interface elements. The display module 174 can also be configuredto display instructions, warnings, errors, measurements, andcalculations.

FIG. 19 illustrates an exemplary graphical user interface 176 that canbe displayed to the user by the display module 174 and through which auser can supply information to the user input module 172. Theillustrated interface 176 is configured for use with a pump system 106that includes first and second motors or linear actuators that can beoperated to apply a force to respective syringe pumps for deliveringinfusate to the catheter 102 and for withdrawing or aspirating fluidfrom the catheter.

The user interface 176 can include a motor communication panel 178 fordisplaying various information associated with the motors. Thisinformation can include the connection status of the motors, an IP orother software address of the motors, and a motor communicationfrequency or update time. The user can interact with the motorcommunication panel 178 to select or change the motor addresses and theupdate time.

The user interface 176 can include a motor setting panel 180 foradjusting various motor settings and for displaying the current settingto the user. The motor setting panel 180 can include controls for themotor velocity, motor acceleration, distance of syringe movement as afunction of motor steps, current motor positions, infusion frequency,infusion amplitude, infusion rate, infusion phase, and so forth.

The controller 104 can be configured to control various infusion and/oraspiration parameters to achieve customized delivery. This can allow thedelivery to be tailored based on the therapeutic application. Exemplaryparameters that can be controlled by the controller 104 include infusiontype, infusion rate, infusion volume, time between infusions,oscillatory rate, infusion and withdraw ratio, infusion phase timing,aspiration type, aspiration rate, time between aspirations, aspirationvolume, and so forth.

The pump or actuator system 106 can be configured to supply a drug or adrug-containing fluid to the catheter 102 and/or to aspirate fluid fromthe catheter. The system 106 can include one or more pumps. For example,the system 106 can include a plurality of pumps, each being associatedwith and in fluid communication with a corresponding lumen of thecatheter 102. The pumps can also be associated with and in fluidcommunication with respective reservoirs for holding a volume of fluid.In some embodiments, the system 106 can include first and second syringepumps coupled to electronic linear actuators configured to advance orretract the plungers of the syringe pumps in response to control signalsreceived from the controller 104. In some embodiments, the system 106can include a peristaltic pump, an auger pump, a gear pump, a pistonpump, a bladder pump, etc. One or more portions of the system 106 can beimplanted in the patient. The system 106 can include any of a variety ofimplantable or extracorporeal pumps. In some embodiments, the system 106can include a fully-implanted, programmable pump and a fully-implantedfluid reservoir containing fluid to be delivered using the system. Insome embodiments, the entire system 106 can be implantable, e.g., tofacilitate chronic treatment methods.

The sensor 108 can be a single sensor or a plurality of sensors.Exemplary sensors include pressure sensors, electrocardiogram sensors,heart rate sensors, temperature sensors, PH sensors, respiration ratesensors, respiration volume sensors, lung capacity sensors, chestexpansion and contraction sensors, intrathoracic pressure sensors,intraabdominal pressure sensors, and the like. One or more of thesensors 108 can be implanted in the patient. One or more of the sensors108 can be mounted on, inserted through, or formed in or on the catheter102. The sensors 108 can also be remote from the catheter 102. In someembodiments, the sensors 108 can include a pressure sensor disposed inor on the catheter 102 for measuring CSF pressure adjacent to thecatheter and an ECG sensor for measuring the patient's heart rate. Thesensors 108 can be connected (via wires or via a wireless connection) tothe sensor input module 168 of the controller 104.

As noted above, one or more components of the delivery system 100 and,in some embodiments, all components of the delivery system, can beimplanted in the patient. Implanting some or all of the delivery system100 can facilitate chronic or long-term drug delivery (e.g., over aperiod of days, weeks, months, or years) via non-invasive or outpatientprocedures.

FIGS. 20A-20B illustrate the catheter 102 fully-implanted in a patient.As shown, the catheter 102 can be configured for positioning within apatient's intrathecal space and can extend substantially the entirelength of the spinal column or along any portion thereof. The catheter102 can include one or more fluid lumens. The catheter 102 can alsoinclude one or more fluid ports. In some embodiments, the catheter 102can include a plurality of fluid lumens, with each of the plurality offluid lumens having its own respective fluid port. In the illustratedembodiment, the catheter 102 includes three fluid lumens and threerespective fluid ports 122P, 122M, and 122D. The catheter 102 can alsoinclude one or more sensors 108 (e.g., pressure sensors). In theillustrated embodiment, each of the fluid ports 122P, 122M, 122Dincludes a sensor 108P, 108M, 108D mounted adjacent or in proximitythereto. A proximal end of the catheter 102 can be coupled to a fullyimplanted, transcutanous, or extracorporeal infusion port 182 throughwhich fluid can be delivered to (or removed from) the various lumens ofthe catheter and through which one or more sensors 108 on the cathetercan be coupled to a controller 104 or other device. A quick-connectorsystem 184 can be used to couple the catheter 102 to the infusion port182. The micro-connector 184 can include air and/or bacterial filtersand can be a zero-dead-volume connector. The pump 106 and the controller104 can be mounted together in a chassis or housing 188, as shown inFIG. 20C, which can be coupled to an injector 190 configured to matewith the infusion port 182. The injector 190 can include magneticalignment features 186 for ensuring that the injector is properlyaligned with respect to a subcutaneous infusion port 182.

As shown in FIG. 20D, the distal or cranial/cervical tip of the catheter102 can have a modified shape to encourage turbulent flow therethrough(e.g., a helical or corkscrew shaped lumen or fluid port 122D asdescribed above). Any of a variety of other shapes can be used. Theother ports 122M, 122P can be similarly configured, can have a simplecircular cross-section as shown in FIG. 20E, or can have any otherconfiguration described herein.

The system 100 illustrated in FIGS. 20A-20E can be used in acute and/orchronic applications in any of a variety of ways.

For example, the catheter 102 can be used to deliver three differentdrugs (e.g., one drug through each different lumen of the catheter).

By way of further example, the catheter 102 can be used for localizeddelivery of different drugs to different areas of the spine.

As yet another example, the catheter 102 can be used to deliver the samedrug with substantially instantaneous distribution along the entirespinal column.

In another example, one port of the catheter 102 can be used to aspiratewhile another is used to infuse in order to draw the infused fluidthrough the spinal canal. In some embodiments, fluid can be infusedthrough a lower-lumbar port 122P and fluid can be aspirated through acervical port 122D to “pull” the infused fluid up the spinal column.

In another example, fluid can be infused through a port 122D disposed inthe cervical region of the patient's spine to propel infused drug intothe cranial space.

By way of further example, the catheter 102 can be used to substantiallycontain an infused drug to a given area of the spine. In someembodiments, fluid can be infused through a lower-lumbar port 122P andfluid can be withdrawn from a mid-lumbar port 122M to keep the infuseddrug between the two ports 122P, 122M in the lumbar region of thepatient's spine.

In an exemplary method, infusions and aspirations via multiple lumensand ports can be staged or combined in a sequence to create and advancea significant bolus at improved, controlled, and convenient rates. Themethod can include simultaneous aspiration/infusion between deliberatelyspaced ports. The delivery can be enhanced by a preparation step ofremoving a safe amount of CSF to be replaced in later procedure stepswhen advancing the bolus. The method can include a final stage ofsynchronized pulsatile infusion. The method can allow a large bolus tobe formed more quickly, can allow controlled dosing, and/or can allowthe bolus to be delivered closer to the brain or other target site. Themethod can be performed using a catheter that tapers from the proximalend towards the distal end. A tapered catheter profile in which thecatheter diameter reduces distal of each port can enable the catheter tobe longer, be easier to introduce/navigate, and have device reachsignificantly closer to the target site. Port designs and locations canbe optimized based on dose and other factors. The catheter can be placedsuch that fluid exiting the ports flows against patient anatomy (e.g., ablind lumen end, lumen sidewall, or lumen constriction) to promoteturbulent flow of the infusate upon exiting the catheter. In an initialstep, a volume of patient CSF can be aspirated through one or more portsof the catheter. In an exemplary embodiment, about 10% by volume of thepatient's CSF can be aspirated through the catheter and stored in areservoir. The amount of CSF that is aspirated can be based on aclinically-determined safe level. In a subsequent delivery step, CSF canbe aspirated from the patient through a distal fluid port 122D of thecatheter 102 while a drug is simultaneously infused into the patientthrough a middle port 122M of the catheter. This can cause a bolus ofdrug to form between the middle and distal ports 122M, 122D. The portscan be located along the length of the catheter to define the bolus sizeor dose. In an advancement step, the bolus of drug can be advancedwithin the patient. This can be achieved by infusingpreviously-aspirated CSF from the reservoir into the patient through aproximal port 122P of the catheter 102. This infusion can urge the bolusdistally towards the target site and can continue until normal or safeCSF pressure is reached within the patient. While previously-aspiratedCSF is used to advance the bolus in the above example, other fluid canbe used instead or in addition, such as drug-containing fluid. Before,during, or after advancement of the bolus, infusion of CSF and/ordrug-containing fluid can be performed in a pulsatile manner incoordination with one or more physiological parameters of the patient.The above method can also be performed using only a proximal port 122Pand a distal port 122D. The proximal, middle, and distal ports 122P,122M, 122D can be spaced along the length of the spinal column as shownin FIG. 20A, or can all be contained in a discrete region of the spine(e.g., the cervical spine, the thoracic spine, the lumbar spine, etc.).

The systems disclosed herein can be used in any of a variety of drugdelivery methods.

In an exemplary method, the infusion pump 106 can be configured to pumpa drug or a drug-containing fluid through the catheter 102 and into apatient (e.g., into an intrathecal space of the patient). The catheter102 can be inserted into the patient at any of a variety of locations.For example, a percutaneous puncture can be formed in the patient usinga needle. The puncture can be formed in the lumbar region of the spine,or in any other region of the spine, e.g., the cervical region betweenC1 and C2. The needle can have a bent distal tip that helps steer thecatheter 102 to be parallel to the spinal cord. The catheter 102 can beinserted through the needle and guided through the intrathecal spacealong the spinal cord. The infusion can be performed in proximity to thepercutaneous puncture, or the catheter 102 can be advanced some distancewithin the patient. In some embodiments, the catheter 102 can beinserted in the lumbar spine and advanced to the cervical spine or tothe cisterna magna. Infusion can be performed at any point along thelength of the catheter 102. Fluid can be infused from a distal end ofthe catheter 102 (e.g., in a cervical region of the spine), the cathetercan be withdrawn proximally, and further infusion can be performed at amore caudal location (e.g., in a lumbar region of the spine).

The pump 106 can be controlled by the controller 104 to synchronize orotherwise coordinate delivery of the drug with the patient's natural CSFflow or pulsation, or with other physiological parameters of the patient(e.g., heart rate, respiration rate, lung capacity, chest expansion andcontraction, intrathoracic pressure, intraabdominal pressure, etc.). Theinfusion profile can be tailored to override the natural CSF pulsationto drive the infusate to a target site. Alternatively, or in addition,the infusion profile can be tailored to coordinate with and leverage thenatural CSF pulsation to move the infusate towards the target site.

Readings from a pressure sensor 108 can be received by the controller104, which can perform signal processing on the sensor output todetermine various characteristics of the patient's CSF flow (e.g.,phase, rate, magnitude, etc.). The controller 104 can then control thepump 106 based on these measured characteristics to deliver a drug incoordination with the natural CSF flow, optionally synchronizing thedelivery in real time. For example, as shown in the upper portion ofFIG. 21A, the controller 104 can convert the measured pulsatile flow ofthe CSF into a sinusoidal approximation. The controller 104 can thenoutput a pump control signal, as shown in the lower portion of FIG. 21A,to drive the infusion pump 106 in coordination with the CSF pulsation.

In some instances, the pressure sensed by the pressure sensor 108 can beinfluenced by the infusion through the catheter 102. Accordingly, it canbe desirable to have another way of detecting or estimating CSF flow.Thus, in some embodiments, the system 100 can be operated initially in a“learning” mode in which no infusion takes place and the controller 104establishes a correlation between CSF pulsation and heart rate (e.g., asdetected by an ECG sensor 108 in communications coupling with thecontroller). In general, CSF pulsation tracks heart rate with a slightdelay. Once a correlation is established, the system 100 can be operatedin an “infusion” mode in which infusate is delivered through thecatheter 102 and the CSF pulsation is detected or estimated based onmeasured heart rate (instead of or in addition to detecting orestimating the CSF pulsation based on the pressure sensor 108 output).In other words, the system 100 can interpolate or estimate the CSF flowbased on the ECG output, without necessarily having to rely on thepressure sensor output. This can allow the pressure sensor to be usedfor other purposes, such as monitoring the infusion pressure to allowthe controller 104 to automatically regulate delivery to a targetpressure or pressure range.

In one example use of the systems described herein, a drug can bedelivered to the intrathecal space via a simple bolus injection (a fastinfusion of a volume of fluid) which then just diffuses slowly along thespinal column.

In another example, a bolus injection can be performed to deliver thedrug and then the system can be used to create a pulsation behind thebolus by changing oscillation rate/pulsation rate to override thenatural CSF pulse and make the bolus move more quickly towards a targetlocation (e.g., the brain). The pulsation can be created by repeatedlywithdrawing or aspirating a volume of CSF and then pumping that samevolume back into the patient to create a pulse.

In another example, infusion of the drug itself can be used to create apulsation effect to urge the drug along the intrathecal space. In thisexample, a first volume of the drug can be infused (e.g., 0.1 ml) andthen a second, smaller volume can be withdrawn (e.g., 0.05 ml). This canbe repeated to create a pulse with a net infusion on each cycle. Theprocess can be repeated until the desired dose is delivered. While aninfusion-to-withdrawal ratio of 2:1 is discussed above, it will beappreciated that any ratio can be used. In addition, the rate ofinfusion and withdrawal can be controlled (e.g., by infusing quickly andwithdrawing slowly) to create a burst of fluid towards a target location(e.g., the top of the spinal column).

In the devices and methods disclosed herein, infusion and/or aspirationcan be coordinated with one or more physiological parameters of apatient (e.g., natural CSF flow, heart rate, respiration rate, etc.).

The direction of drug distribution at an intrathecal target site can becontrolled at least to some degree based on the timing at which the drugis delivered relative to the timing of the CSF flow. For example,infusion that is synchronized with the ascending wave of CSF flow, asshown in FIG. 21B, can be distributed to a greater degree in the cranialdirection whereas infusion that is synchronized with the descending waveof CSF flow, as shown in FIG. 21C, can be distributed to a greaterdegree in the caudal direction of the spinal canal.

In some embodiments, a dual- or multi-lumen catheter can be used foralternating, repetitive infusion and aspiration, which can furtherenhance drug distribution.

The systems and methods disclosed herein can provide an improved meansfor delivering a drug to the intrathecal space, as compared withtraditional lumbar bolus injections which do not reach the remoteportions of the spinal canal or brain efficiently (if at all).

While intrathecal delivery is generally described in the examples givenabove, it will be appreciated that the systems and methods herein can beused in other applications, with appropriate modification of size orother parameters as will be appreciated by those having ordinary skillin the art. For example, the systems and methods disclosed herein can beused for intraarterial or intravenous delivery. Such systems and methodscan include infusion and/or aspiration that is coordinated with one ormore physiological parameters of a patient (e.g., natural CSF flow,heart rate, respiration rate, etc.).

In some embodiments, the drug can be delivered in a non-pulsatile mannerand/or without necessarily coordinating the delivery with aphysiological parameter of the patient. For example, alternating orotherwise-coordinated aspiration and infusion can be used to deliver thedrug to a target site. By way of further example, the drug can beinfused and then a buffer can be infused behind the drug to enhancedistribution or to move the drug towards a target site.

An exemplary method can include inserting at least a portion of acatheter into a patient and delivering a drug to a target region of thepatient. At least a portion of the catheter can be disposed in thetarget region. The drug can be delivered in a pulsatile manner. The drugcan be delivered in coordination with a physiological parameter of thepatient (e.g., the patient's natural CSF flow and/or the patient's heartrate).

The target region can be an intrathecal space of the patient. The targetregion can be a subpial region of the patient (e.g., a subpial region ofthe spinal cord and/or a subpial region of the brain). The target regioncan be a cerebellum of the patient. The target region can be a dentatenucleus of the patient. The target region can be a dorsal root ganglionof the patient. The target region can be a motor neuron of the patient.The drug can include an antisense oligonucleotide. The drug can includea stereopure nucleic acid. The drug can include a virus. The drug caninclude adeno-associated virus (AAV). The drug can include a non-viralgene therapy. The drug can include vexosomes. The drug can includeliposomes. The method can include performing gene therapy by deliveringthe drug (e.g., by delivering a virus such as AAV). The method caninclude performing gene editing by delivering the drug (e.g., bydelivering a virus such as AAV). The method can include performing geneswitching by delivering the drug (e.g., by delivering a virus such asAAV). The method can include performing non-viral gene therapy bydelivering the drug (e.g., by delivering vexosomes and/or liposomes).

In some embodiments, the method can include determining a total CSFvolume of the patient and tailoring the delivery based on the total CSFvolume. For example, MRI or other imaging techniques, with or withoutcontrast, can be used to assess the overall CSF volume of the patient.The delivery of the drug can then be tailored based on the measuredvolume. For example, a larger volume of buffer can be used with patientshaving a greater total CSF volume and a smaller volume of buffer can beused with patients having a lesser total CSF volume. By way of furtherexample, infusion amplitude, infusion velocity, aspiration volume,aspiration amplitude, and other parameters can be varied in accordancewith the measured total CSF volume.

The infusion volume can range from about 0.05 mL and about 50 mL. Theinfusion rate can range from about 0.5 mL/min to about 50 mL/min.

The following are exemplary drug delivery methods that can be performedusing the systems disclosed herein:

Example A

Alternating Pulsatile infusions of Drug (Pump 1) and Buffer/Saline (Pump2)

Drug Total Volume: 2.2 mL

Buffer Total Volume: 4.4 mL

Infusion rate for both pumps: 15 mL/min

Cycles: 10 cycles at lumbar then 10 cycles at Cisterna magna

Time between cycles: 100 milliseconds

Infusion description: At lumbar section Pump 1 infuses 0.11 mL at 15mL/min, a 100 ms pause, Pump 2 infuses 0.22 mL at 15 mL/min, a 100 mspause (cycle 1). This is repeated for a total of 10 cycles at thelumbar. Catheter is threaded up to the cisterna magna. Pump 1 infuses0.11 mL at 15 mL/min, a 100 ms pause, Pump 2 infuses 0.22 mL at 15mL/min, a 100 ms pause (cycle 1). This is repeated for a total of 10cycles at the cisterna magna.

Example B

Alternating Pulsatile infusions of Drug (Pump 1) and Buffer/Saline (Pump2)

Drug Total Volume: 3 mL

Buffer Total Volume: 20 mL

Infusion rate for both pumps: 4 mL/min

Cycles: 13 cycles at thoracic region

Time between alternating pump 1 to pump 2: 1000 milliseconds

Time between cycles (pump 2 to pump 1): 5000 milliseconds

Infusion description: At lumbar section Pump 1 infuses 0.231 mL at 4mL/min, a 1000 ms pause, Pump 2 infuses 2.0 mL at 4 mL/min, a 5000 mspause (cycle 1). This is repeated for a total of 13 cycles at thethoracic region.

Example C

Alternating Pulsatile infusions of Drug (Pump 1) and Buffer/Saline (Pump2)

Drug Total Volume: 5 mL

Buffer Total Volume: 8 mL

Infusion rate for pump 1: 37 mL/min

Infusion rate for pump 2: 20 mL/min

Cycles: 5 cycles at thoracic region

Time between cycles: 10 milliseconds

Infusion description: At lumbar section Pump 1 infuses 1 mL at 37mL/min, a 10 ms pause, Pump 2 infuses 1.6 mL at 30 mL/min, a 100 mspause (cycle 1). This is repeated for a total of 5 cycles at thethoracic region.

FIG. 22 illustrates a drug delivery system 200 that includes a lumbarpuncture needle 292. The needle 292 can include a sensor 294 (e.g., apressure sensor) mounted adjacent a distal tip of the needle.Accordingly, upon insertion of the needle 292 into the patient 210, thesensor 294 can measure the pressure or other properties of the patient'sCSF. The needle 292 can also include an integrated or remote display 296for displaying the output of the sensor 294 to a user. In someembodiments, the display 296 can be mounted along the length of theneedle 292, distal to a proximal Luer or other connector 298 of theneedle. The needle body 292 can be a tubular metal shaft with asharpened or angled tip. Fluid tubing can be coupled to the needle 292,e.g., via a proximal connector 298, and to a programmable pump 106. Acontroller 104 of the type described above can be programmed to controlthe pump 106 to deliver fluid through the needle 292, e.g., in apulsatile fashion in coordination with a physiological parameter of thepatient. The needle 292 can be used to deliver a drug, to deliver abuffer, and/or to aspirate fluid. In some embodiments, a catheter 102 ofthe type described above can be inserted through the needle 292 and thefluid delivery or aspiration can be performed through the catheter.

As shown in FIG. 23, a manual pump 206 can be provided instead of or inaddition to the programmable pump 106 and controller 104 shown in FIG.22. As shown, a first fluid lumen of the needle 292 (or of a catheter102 inserted through the needle) can be coupled to a first pump 206Athat includes a first reservoir and a first flush dome. Similarly, asecond fluid lumen of the needle 292 (or of a catheter 102 insertedthrough the needle) can be coupled to a second pump 206B that includes asecond reservoir and a second flush dome. A user can exert manual fingerpressure on the first and second flush domes to selectively press fluidcontained in the first and second reservoirs into the patient.Accordingly, the user's manual actuation rate and actuation pressure candictate the infusion frequency and volume. A user can thus pulse thedelivery manually. The flush domes can be configured such that eachsuccessive actuation of the dome delivers a fixed and predeterminedvolume of fluid. For example, each push of the flush dome can beconfigured to deliver 0.1 ml of fluid. In some embodiments, one of thereservoirs can be filled with a buffer solution and the other reservoircan be filled with a drug-containing solution.

Although the invention has been described by reference to specificembodiments, it should be understood that numerous changes may be madewithin the spirit and scope of the inventive concepts described.Accordingly, it is intended that the invention not be limited to thedescribed embodiments.

1-69. (canceled)
 70. A method of delivering a drug to a patient,comprising: inserting a delivery device into an intrathecal space of thepatient; infusing a drug through delivery device and into theintrathecal space; and after infusing the drug, infusing a fluid behindthe drug such that infusion of the fluid enhances distribution of thedrug or moves the drug towards a target site within the patient.
 71. Themethod of claim 70, wherein the infusion of the fluid overrides thenatural CSF pulsation or flow of the patient to urge the drug towardsthe target site.
 72. The method of claim 70, wherein the infusion of thefluid coordinates with the natural CSF pulsation or flow of the patientto urge the drug towards the target site.
 73. The method of claim 70,wherein the fluid comprises at least one of a drug, a buffer solution,and CSF aspirated from the patient through the delivery device.
 74. Themethod of claim 70, wherein at least one of the infusion of the drug andthe infusion of the fluid is coordinated with a physiological parameterof the patient.
 75. The method of claim 74, wherein the physiologicalparameter is at least one of heart rate, intrathecal pressure,intrathecal pulsation rate, respiration rate, lung capacity, chestexpansion, chest contraction, intrathoracic pressure, and intraabdominalpressure.
 76. The method of claim 70, further comprising aspirating avolume of CSF from the patient, wherein the infused fluid comprises theaspirated CSF.
 77. The method of claim 70, wherein the target site is atleast one of an intrathecal space of the patient, a subpial region ofthe patient, a cerebellum of the patient, a dentate nucleus of thepatient, a dorsal root ganglion of the patient, and a motor neuron ofthe patient.
 78. The method of claim 70, wherein the target site is aneuronal structure of the patient.
 79. The method of claim 70, whereinthe drug includes at least one of an antisense oligonucleotide, astereopure nucleic acid, a virus, adeno-associated virus (AAV),non-viral gene therapy, vexosomes, and liposomes.
 80. The method ofclaim 70, wherein the method includes at least one of performing genetherapy by delivering the drug, performing gene editing by deliveringthe drug, performing gene switching by delivering the drug, andperforming non-viral gene therapy by delivering the drug.
 81. The methodof claim 70, further comprising determining a total CSF volume of thepatient and tailoring the infusion of the fluid based on the total CSFvolume.
 82. The method of claim 70, further comprising measuring aphysiological parameter of the patient using a sensor and, with thecontroller, controlling the pump to coordinate infusion of the fluidthrough the delivery device with the physiological parameter measured bythe sensor.
 83. The method of claim 82, further comprising synchronizinginfusion frequency with a frequency of the patient's natural intrathecalpulsation as measured by the sensor.
 84. The method of claim 82, furthercomprising synchronizing infusion phase with a phase of the patient'snatural intrathecal pulsation as measured by the sensor.
 85. The methodof claim 82, further comprising establishing a sinusoidal approximationof the patient's natural intrathecal pulsation as measured by the sensorand synchronizing infusions with an ascending wave of the sinusoidalapproximation.
 86. The method of claim 82, further comprisingestablishing a sinusoidal approximation of the patient's naturalintrathecal pulsation as measured by the sensor and synchronizinginfusions with a descending wave of the sinusoidal approximation. 87.The method of claim 82, wherein the sensor is configured to measureintrathecal pressure.
 88. The method of claim 82, wherein the sensorcomprises a first sensor configured to measure intrathecal pressure anda second sensor configured to measure heart rate.
 89. The method ofclaim 70, wherein the delivery device is inserted through a percutaneouslumbar puncture in the patient.